Objective To investigate the effects of bisdemethoxycurcumin(BDMC) on non-small cell lung cancer(NSCLC) cell line, A549, and the highly metastatic lung cancer 95 D cells. Methods CCK-8 assay was used to assess the eff...Objective To investigate the effects of bisdemethoxycurcumin(BDMC) on non-small cell lung cancer(NSCLC) cell line, A549, and the highly metastatic lung cancer 95 D cells. Methods CCK-8 assay was used to assess the effect of BDMC on cytotoxicity. Flow cytometry was used to evaluate apoptosis. Western blot analysis, electron microscopy, and quantification of GFP-LC3 punctuates were used to test the effect of BDMC on autophagy and apoptosis of lung cancer cells. Results BDMC inhibited the viability of NSCLC cells, but had no cytotoxic effects on lung small airway epithelial cells(SAECs). The apoptotic cell death induced by BDMC was accompanied with the induction of autophagy in NSCLC cells. Blockage of autophagy by the autophagy inhibitor 3-methyladenine(3-MA) repressed the growth inhibitory effects and induction of apoptosis by BDMC. In addition, BDMC treatment significantly decreased smoothened(SMO) and the transcription factor glioma-associated oncogene 1(Gli1) expression. Furthermore, depletion of Gli1 by si RNA and cyclopamine(a specific SMO inhibitor) induced autophagy. Conclusion Aberrant activation of Hedgehog(Hh) signaling has been implicated in several human cancers, including lung cancers. The present findings provide direct evidence that BDMC-induced autophagy plays a pro-death role in NSCLC, in part, by inhibiting Hedgehog signaling.展开更多
Apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand(TRAIL) can be regulated by the epidermal growth factor(EGF) signaling pathway.In this study,recombinant adenoviral vectors that encode TRAIL...Apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand(TRAIL) can be regulated by the epidermal growth factor(EGF) signaling pathway.In this study,recombinant adenoviral vectors that encode TRAIL gene from the hTERT/RGD promoter(AdTRAIL) was combined with drugs including gefitinib,elotinib,and cetuximab that inhibit EGFR and the EGF signaling pathway in non-small cell lung cancer(NSCLC) cell lines to investigate their antitumor activity.In vitro,compared to single reagent,AdTRAIL combined with EGFR inhibitors reduced proliferation and enhanced apoptosis in H460,A549,and SW1573 cell lines.Western blot results suggested that these effects were relative to up-regulation of pro-apoptosis protein BAX and down-regulation of p-AKT.In vivo,AdTRAIL combined with cetuximab resulted in a significant growth reduction in H460 xenografts without damage to the main organs of nude mice.Histological examination and TUNEL analyses of xenografts showed that cetuximab enhanced cell apoptosis induced by AdTRAIL.These results indicate that EGFR inhibitors enhanced AdTRAIL anti-tumor activity in NSCLC cell lines and that inhibiting the AKT pathway played an important role in this enhancement.展开更多
Background:Apelin,an endogenous ligand of G-protein coupled receptor(GPCR),is a secreted peptide involved in the development of various tumors.However,the relationship between apelin and non-small cell lung cancer(NSC...Background:Apelin,an endogenous ligand of G-protein coupled receptor(GPCR),is a secreted peptide involved in the development of various tumors.However,the relationship between apelin and non-small cell lung cancer(NSCLC)is not quite clear.This study was designed to investigate the effect and mechanism of apelin on cell proliferation,migration and invasion of NSCLC cells.Methods:Twelve NSCLC specimens were collected for hematoxylin-eosin(HE)staining and immunohistochemistry analyses.Cell proliferation was examined by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)and cell migration and invasion were assessed using wound-healing and transwell assays.The subcellular location of yes associated protein 1(YAP1)in A549 cells was determined by immunofluorescence.The mRNA and protein levels in NSCLC tissues and cell lines were measured by qRT-PCR and western blot,respectively.Results:Apelin was upregulated in tumor tissues compared with the adjacent tissues.Apelin promoted proliferation,migration,and invasion of A549 and H460 cells,which was reversed by competitive apelin receptor(APJ)antagonist ML221.Additionally,apelin upregulated YAP1 expression,whereas silence of YAP1 by small interfering RNA(siRNA)attenuated apelin-induced cell proliferation,migration and invasion and suppressed epithelial-mesenchymal transition progression.Conclusion:Apelin promotes NSCLC cells proliferation,migration,and invasion by modulating YAP1 and might be a potential therapeutic target for NSCLC treatment.展开更多
Objective The aim of this study was to explore the mechanism behind lncRNA small nucleolar RNA host gene 19(lncRNA SNHG19)/microrNA-299-5P(miR-299-5p)/mitogen-activated protein kinase 6(MAPK6)signaling axis promoting ...Objective The aim of this study was to explore the mechanism behind lncRNA small nucleolar RNA host gene 19(lncRNA SNHG19)/microrNA-299-5P(miR-299-5p)/mitogen-activated protein kinase 6(MAPK6)signaling axis promoting metastasis of non-small cell lung cancer(NSCLC).Methods To analyze the abnormal expression of lncRNAs in NSCLC,50 surgically resected NSCLC and adjacent tissue samples were collected from August 2021 to August 2022.The mRNA expression levels of lncRNA SNHG19,Mir-299-5p,and MAPK6 were detected by qRT-PCR.The functions of lncRNA SNHG19,Mir-299-5p and MAPK6 were investigated by CCK-8,clone formation,EdU,scratch,Transwell western blotting(WB)and in vivo xenograft assay.RNA fluorescence in-situ hybridization(FISH),RNA pull-down,dual luciferase reporter,and RNA co-immunoprecipitation assays were used to explore the mechanism of action between lncRNA SNHG19,miR-299-5p,and MAPK6.Results High expression of lncRNA SNHG19 was correlated with poor prognosis,tumor size,lymph node metastasis,and TNM stage in NSCLC patients(P<0.05).Cell function experiments showed that lncRNA SNHG19 could improve the proliferation,clone formation,migration,and invasion ability of A549 cells both in vitro and in vivo(all P<0.05)and increased the relative expression levels of vimentin and MAPK6(P<0.05).The relative expression level of E-cadherin was decreased(P<0.05).lncRNA SNHG19 can interact with Mir-299-5p and regulate the expression level of MAPK6.Conclusion lncRNA SNHG19 is upregulated in NSCLC tissues and cells,and its high expression is associated with tumor progression and poor survival.Moreover,it can act as a molecular sponge for Mir-299-5p to regulate MAPK6 expression and promote the proliferation and metastasis of A549 cells.展开更多
Purpose Lung cancer is one of the most aggressive cancer types, and is the leading cause of cancer-related deaths worldwide. Isothiocyanates are natural compounds found in
Patients with epidermal growth factor receptor(EGFR)wild-type non-small cell lung cancer(NSCLC)often show primary resistance to gefitinib therapy.It is thus necessary to study the metabolism of gefitinib in NSCLC cell...Patients with epidermal growth factor receptor(EGFR)wild-type non-small cell lung cancer(NSCLC)often show primary resistance to gefitinib therapy.It is thus necessary to study the metabolism of gefitinib in NSCLC cells to comprehensively reveal the reasons for the primary resistance of tumors.Herein,we develop a platform for studying drug metabolism heterogeneity based on single-cell mass spectrometry(sDMH-scMS)by integrating living-cell electrolaunching ionization MS(ILCEI-MS)and high-performance liquid chromatography-MS(HPLC-MS)analysis,and the primary resistance of NSCLC cells to gefitinib was studied using this platform.The ILCEI-MS analysis showed that approximately 11.9%of NSCLC single cells contained the gefitinib metabolite M11;HPLC-MS detection diluted the intensity of M11 in subpopulations and concealed the heterogeneity of drug metabolism in tumor single cells.The intensity of gefitinib in EGFR wild-type A549 cells was markedly lower than in mutant PC9 cells,and the intensity of gefitinib metabolites was significantly higher than in PC9 cells,suggesting that the primary resistance of NSCLC cells is related to gefitinib metabolism.Moreover,the combination of gefitinib and the drug-metabolizing enzyme inhibitorα-naphthoflavone was shown to overcome the primary resistance of the NSCLC cells.Overall,the results of this study are expected to be applicable for clinical drug resistance diagnosis and treatment at the single-cell level.展开更多
Objective This study aimed to investigate the changes of follicular helper T(TFH)and follicular regulatory T(TFR)cell subpopulations in patients with non-small cell lung cancer(NSCLC)and their significance.Methods Per...Objective This study aimed to investigate the changes of follicular helper T(TFH)and follicular regulatory T(TFR)cell subpopulations in patients with non-small cell lung cancer(NSCLC)and their significance.Methods Peripheral blood was collected from 58 NSCLC patients at different stages and 38 healthy controls.Flow cytometry was used to detect TFH cell subpopulation based on programmed death 1(PD-1)and inducible co-stimulator(ICOS),and TFR cell subpopulation based on cluster determinant 45RA(CD45RA)and forkhead box protein P3(FoxP3).The levels of interleukin-10(IL-10),interleukin-17a(IL-17a),interleukin-21(IL-21),and transforming growth factor-β(TGF-β)in the plasma were measured,and changes in circulating B cell subsets and plasma IgG levels were also analyzed.The correlation between serum cytokeratin fragment antigen 21-1(CYFRA 21-1)levels and TFH,TFR,or B cell subpopulations was further explored.Results The TFR/TFH ratio increased significantly in NSCLC patients.The CD45RA^(+)FoxP3^(int) TFR subsets were increased,with their proportions increasing in stages Ⅱ to Ⅲ and decreasing in stage IV.PD-1^(+)ICOS+TFH cells showed a downward trend with increasing stages.Plasma IL-21 and TGF-β concentrations were increased in NSCLC patients compared with healthy controls.Plasmablasts,plasma IgG levels,and CD45RA^(+)FoxP3^(int) TFR cells showed similar trends.TFH numbers and plasmablasts were positively correlated with CYFRA 21-1 in stages Ⅰ-Ⅲ and negatively correlated with CYFRA 21-1 in stage IV.Conclusion Circulating TFH and TFR cell subpopulations and plasmablasts dynamically change in different stages of NSCLC,which is associated with serum CYFRA 21-1 levels and reflects disease progression.展开更多
BACKGROUND This study was designed to investigate the clinical outcomes of enhanced recovery after surgery(ERAS)in the perioperative period in elderly patients with nonsmall cell lung cancer(NSCLC).AIM To investigate ...BACKGROUND This study was designed to investigate the clinical outcomes of enhanced recovery after surgery(ERAS)in the perioperative period in elderly patients with nonsmall cell lung cancer(NSCLC).AIM To investigate the potential enhancement of video-assisted thoracic surgery(VATS)in postoperative recovery in elderly patients with NSCLC.METHODS We retrospectively analysed the clinical data of 85 elderly NSCLC patients who underwent ERAS(the ERAS group)and 327 elderly NSCLC patients who received routine care(the control group)after VATS at the Department of Thoracic Surgery of Peking University Shenzhen Hospital between May 2015 and April 2017.After propensity score matching of baseline data,we analysed the postoperative stay,total hospital expenses,postoperative 48-h pain score,and postoperative complication rate for the 2 groups of patients who underwent lobectomy or sublobar resection.RESULTS After propensity score matching,ERAS significantly reduced the postoperative hospital stay(6.96±4.16 vs 8.48±4.18 d,P=0.001)and total hospital expenses(48875.27±18437.5 vs 55497.64±21168.63 CNY,P=0.014)and improved the satisfaction score(79.8±7.55 vs 77.35±7.72,P=0.029)relative to those for routine care.No significant between-group difference was observed in postoperative 48-h pain score(4.68±1.69 vs 5.28±2.1,P=0.090)or postoperative complication rate(21.2%vs 27.1%,P=0.371).Subgroup analysis showed that ERAS significantly reduced the postoperative hospital stay and total hospital expenses and increased the satisfaction score of patients who underwent lobectomy but not of patients who underwent sublobar resection.CONCLUSION ERAS effectively reduced the postoperative hospital stay and total hospital expenses and improved the satisfaction score in the perioperative period for elderly NSCLC patients who underwent lobectomy but not for patients who underwent sublobar resection.展开更多
Owing to significantly prolonged survival,targeted therapy has become standardized recommendation for advanced non-small cell lung cancer patients with mutated driver genes.However,the genetic status of lung cancer pa...Owing to significantly prolonged survival,targeted therapy has become standardized recommendation for advanced non-small cell lung cancer patients with mutated driver genes.However,the genetic status of lung cancer patients is dynamic.By dynamically monitoring the evolution of genes status,differential genes and concomitant genes related to progressive disease could be confirmed early,so as to achieve a more accurate and comprehensive insight of the whole process management of targeted therapy for lung cancer patients.Under the guidance of accurate genetic testing results,it is helpful to provide patients with more effective,long-term,and stable individualized targeted therapy.展开更多
Actin, a highly conserved protein, plays a dominant role in Non-small cell lung cancer (NSCLC). Late diagnosis and the aggressive nature of NSCLC pose a significant threat. Studying the clinic pathological properties ...Actin, a highly conserved protein, plays a dominant role in Non-small cell lung cancer (NSCLC). Late diagnosis and the aggressive nature of NSCLC pose a significant threat. Studying the clinic pathological properties of NSCLC proteins is a potential alternative for developing treatment strategies. Towards this, 35 downregulated actin cytoskeletal proteins on NSCLC prognosis and treatment were studied by examining their protein-protein interactions, gene ontology enrichment terms, and signaling pathways. Using PubMed, various proteins in NSCLC were identified. The protein-protein interactions and functional associations of these proteins were examined using the STRING database. The focal adhesion signaling pathway was selected from all available KEGG and Wiki pathways because of its role in regulating gene expression, facilitating cell movement and reproduction, and significantly impacting NSCLC. The protein-protein interaction network of the 35 downregulated actin cytoskeleton proteins revealed that ACTG1, ACTR2, ACTR3, ANXA2, ARPC4, FLNA, TLN1, CALD1, MYL6, MYH9, MYH10, TPM1, TPM3, TPM4, PFN1, IQGAP1, MSN, and ZXY exhibited the highest number of interactions. Whereas HSPB1, CTNNA1, KRT17, KRT7, FLNB, SEPT2, and TUBA1B displayed medium interactions, while UTRN, TUBA1B, and DUSP23 had relatively fewer interactions. It was discovered that focal adhesions are critical in connecting membrane receptors with the actin cytoskeleton. In addition, protein kinases, phosphatases, and adapter proteins were identified as key signaling molecules in this process, greatly influencing cell shape, motility, and gene expression. Our analysis shows that the focal adhesion pathway plays a crucial role in NSCLC and is essential for developing effective treatment strategies and improving patient outcomes.展开更多
Lung cancer is the leading cause of cancer-related deaths globally.In recent years,with the widespread use of genetic testing,epidermal growth factor receptor–tyrosine kinase inhibitor(EGFR-TKI)–targeted drugs have ...Lung cancer is the leading cause of cancer-related deaths globally.In recent years,with the widespread use of genetic testing,epidermal growth factor receptor–tyrosine kinase inhibitor(EGFR-TKI)–targeted drugs have been efficacious to patients with lung adenocarcinoma exhibiting EGFR mutations.However,resistance to treatment is inevitable and eventually leads to tumor progression,recurrence,and reduction in the overall treatment efficacy.Lung cancer stem cells play a crucial role in the development of resistance toward EGFR-TKI–targeted therapy for lung adenocarcinoma.Lung cancer stem cells possess self-renewal,multilineage differentiation,and unlimited proliferation capabilities,which efficiently contribute to tumor formation and ultimately lead to tumor recurrence andmetastasis.In this study,we evaluated the origin,markers,stemness index,relevant classic studies,resistance mechanisms,related signaling pathways,and strategies for reversing lung cancer stem cell resistance to EGFR-TKIs to provide new insights on delaying or reducing resistance and to improve the treatment efficacy of patients with EGFR-mutated lung adenocarcinoma in the future.展开更多
In non-small cell lung cancer(NSCLC),the heterogeneity promotes drug resistance,and the restricted expression of programmed death-ligand 1(PD-L1)limits the immunotherapy benefits.Based on the mechanisms related to tra...In non-small cell lung cancer(NSCLC),the heterogeneity promotes drug resistance,and the restricted expression of programmed death-ligand 1(PD-L1)limits the immunotherapy benefits.Based on the mechanisms related to translation regulation and the association with PD-L1 of methyltransferaselike 3(METTL3),the novel small-molecule inhibitor STM2457 is assumed to be useful for the treatment of NSCLC.We evaluated the efficacy of STM2457 in vivo and in vitro and confirmed the effects of its inhibition on disease progression.Next,we explored the effect of STM2457 on METTL3 and revealed its effects on the inhibition of catalytic activity and upregulation of METTL3 protein expression.Importantly,we described the genome-wide characteristics of multiple omics data acquired from RNA sequencing,ribosome profiling,and methylated RNA immunoprecipitation sequencing data under STM2457 treatment or METTL3 knockout.We also constructed a model for the regulation of the translation of METTL3 and PD-L1.Finally,we found PD-L1 upregulation by STM2457 in vivo and in vitro.In conclusion,STM2457 is a potential novel suppressor based on its inhibitory effect on tumor progression and may be able to overcome the heterogeneity based on its impact on the translatome.Furthermore,it can improve the immunotherapy outcomes based on PDL1 upregulation in NSCLC.展开更多
Objective:To explore the mechanism of tapinarof inhibiting proliferation and promoting apoptosis of non-small cell lung cancer A549 cell.Methods:The proliferative ability of non-small cell lung cancer cells A549 and H...Objective:To explore the mechanism of tapinarof inhibiting proliferation and promoting apoptosis of non-small cell lung cancer A549 cell.Methods:The proliferative ability of non-small cell lung cancer cells A549 and H1299 was detected by clonal formation assay,and the cell viability of non-small cell lung cancer cells A549 was detected by CCK-8 assay.A549 cells were treated with different concentrations of tapinarof(0,5,10,20)μmol/L for 24 h.The effects of tapinarof on the cell cycle of A549 were detected by flow cytometry using PI single dye method.Western blot assay was used to detect the effect of benzene-moder on the expression of cycle-associated protein P21 and CDK2.A549 cells were treated with different concentrations of tapinarof(0,10,20,40)μmol/L for 48 h.Annexin V-FITC and PI double staining were used to detect the effect of tapinarof on apoptosis of A549 cells.Western blot assay was used to detect the effects of different concentrations of tapinarof on expression of apoptosis-related proteins,cleaved-caspase 3 and cleaved-PARP.Western blot analysis was performed to determine the expression of p-AKT and FOXO1 in A549 cells at different concentrations(0,5,10,20)μmol/L.Results:The results of clonal formation experiment showed that 40μmol/L tapinarof could completely inhibit the proliferation of A549 and H1299 cells.CCK-8 assay showed that compared with the control group(0μmol/L),A549 cell activity decreased gradually with the increase of tapinarof concentration.A549 cells were stained with Annexin-FITC/PI.Flow cytometry showed that the apoptosis rate of A549 cells increased with the increase of tapinarof treatment concentration(40μmol/L tapinarof treatment,P<0.001).After treatment with tapinarof for 48 h,the protein expression of cleaved-caspase 3 and cleaved-PARP in A549 cells was increased,compared with control group(0μmol/L).Flow cytometry after PI staining of A549 cells showed that tapinarof induced A549 cell arrest in G1 phase.In A549 cells treated with tapinarof for 24 h,the expression of P21 protein was increased and CDK2 decreased.The phosphorylation level of AKT was significantly inhibited and the expression level of FOXO1 was increased in A549 cells treated with phenylenmode at different concentrations.Conclusion:Tapinarof inhibits the proliferation of A549 cells and induces apoptosis,which may be related to the AKT/FOXO1 signaling pathway.展开更多
Maintenance immunotherapy after concurrent chemoradiotherapy remains the standard therapeutic approach in patients with unresectable locally advanced non-small cell lung cancer(LA-NSCLC).The efficacy of pembrolizumab ...Maintenance immunotherapy after concurrent chemoradiotherapy remains the standard therapeutic approach in patients with unresectable locally advanced non-small cell lung cancer(LA-NSCLC).The efficacy of pembrolizumab without chemotherapy in stage IV NSCLC has incited interest in similar approaches for LA-NSCLC.Several recent investigations involving the synergistic potential of immunotherapy combined with radiotherapy(i RT)have generated encouraging results.This review discusses the existing studies and prospective directions of chemotherapy-free i RT strategies in unresectable LA-NSCLC.Although the initial findings of chemotherapy-free i RT strategies have shown promising efficacy,we must consider the methodologic limitations of current studies and the myriad of challenges that accompany the implementation of chemotherapy-free i RT.These challenges include determining the optimal dose and fractionation,precise target volume delineation,and identification of additional suitable patient cohorts.Furthermore,the feasibility of chemotherapy-free i RT as a novel treatment modality for select patients with LA-NSCLC is contingent upon validation through randomized phase III trials.展开更多
Objective The combination of stereotactic body radiation therapy(SBRT)and immune checkpoint inhibitors(ICIs)is actively being explored in advanced non-small-cell lung cancer(NSCLC)patients.However,little is known abou...Objective The combination of stereotactic body radiation therapy(SBRT)and immune checkpoint inhibitors(ICIs)is actively being explored in advanced non-small-cell lung cancer(NSCLC)patients.However,little is known about the optimal fractionation and radiotherapy target lesions in this scenario.This study investigated the effect of SBRT on diverse organ lesions and radiotherapy dose fractionation regimens on the prognosis of advanced NSCLC patients receiving ICIs.Methods The medical records of advanced NSCLC patients consecutively treated with ICIs and SBRT were retrospectively reviewed at our institution from Dec.2015 to Sep.2021.Patients were grouped according to radiation sites.Progression-free survival(PFS)and overall survival(OS)were recorded using the Kaplan-Meier method and compared between different treatment groups using the log-rank(Mantel-Cox)test.Results A total of 124 advanced NSCLC patients receiving ICIs combined with SBRT were identified in this study.Radiation sites included lung lesions(lung group,n=43),bone metastases(bone group,n=24),and brain metastases(brain group,n=57).Compared with the brain group,the mean PFS(mPFS)in the lung group was significantly prolonged by 13.3 months(8.5 months vs.21.8 months,HR=0.51,95%CI:0.28–0.92,P=0.0195),and that in the bone group prolonged by 9.5 months with a 43%reduction in the risk of disease progression(8.5 months vs.18.0 months,HR=0.57,95%CI:0.29–1.13,P=0.1095).The mPFS in the lung group was prolonged by 3.8 months as compared with that in the bone group.The mean OS(mOS)in the lung and bone groups was longer than that of the brain group,and the risk of death decreased by up to 60%in the lung and bone groups as compared with that of the brain group.When SBRT was concurrently given with ICIs,the mPFS in the lung and brain groups were significantly longer than that of the bone group(29.6 months vs.16.5 months vs.12.1 months).When SBRT with 8–12 Gy per fraction was combined with ICIs,the mPFS in the lung group was significantly prolonged as compared with that of the bone and brain groups(25.4 months vs.15.2 months vs.12.0 months).Among patients receiving SBRT on lung lesions and brain metastases,the mPFS in the concurrent group was longer than that of the SBRT→ICIs group(29.6 months vs.11.4 months,P=0.0003 and 12.1 months vs.8.9 months,P=0.2559).Among patients receiving SBRT with<8 Gy and 8–12 Gy per fraction,the mPFS in the concurrent group was also longer than that of the SBRT→ICIs group(20.1 months vs.5.3 months,P=0.0033 and 24.0 months vs.13.4 months,P=0.1311).The disease control rates of the lung,bone,and brain groups were 90.7%,83.3%,and 70.1%,respectively.Conclusion The study demonstrated that the addition of SBRT on lung lesions versus bone and brain metastases to ICIs improved the prognosis in advanced NSCLC patients.This improvement was related to the sequence of radiotherapy combined with ICIs and the radiotherapy fractionation regimens.Dose fractionation regimens of 8–12 Gy per fraction and lung lesions as radiotherapy targets might be the appropriate choice for advanced NSCLC patients receiving ICIs combined with SBRT.展开更多
Objective:To investigate the prognostic value of radiomics features based on ^(18)F-FDG PET/CT imaging for advanced non-small cell lung cancer(NSCLC)treated with chemotherapy.Methods:A sample of 146 NSCLC patients sta...Objective:To investigate the prognostic value of radiomics features based on ^(18)F-FDG PET/CT imaging for advanced non-small cell lung cancer(NSCLC)treated with chemotherapy.Methods:A sample of 146 NSCLC patients stagedⅢor stageⅣwere included in this retrospective study who received ^(18)F-FDG PET/CT before treatment.All patients were treated with standardized chemotherapy after PET/CT examination and were divided into training group and validation group in an 8:2 ratio randomly.Radiomics features were extracted.In the training group,the minimum absolute contraction and selection operator(LASSO)algorithm and Cox risk proportional regression model were used to screen radiomics and clinical prognostic factors of progression-free survival(PFS).The radiomic model,clinical model and complex model were established respectively.The corresponding scores were calculated,then verified in the validation group.Results:The LASSO algorithm finally screened four radiomics features.ROC results showed that in the training group,the AUC of PFS predicted by the radiomics model was 0.746,and that in the verification group was 0.622.COX multivariate analysis finally included three clinical features related to PFS in NSCLC patients,namely pathological type,clinical stage and MTV30.The AUC for predicting PFS by clinical model,radiomics model and composite model were 0.746,0.753 and 0.716,respectively.The radiomics model had the highest diagnostic efficacy,and its sensitivity and specificity were 0.663 and 0.833,respectively.Delong test verified that there was no statistical difference in the predictive efficacy between the radiomics model and the composite model(Z=1.777,P=0.076)and the clinical imaging model(Z=0.323,P=0.747).Conclusion:The radiomics model based on PET/CT has a good predictive value for the prognosis of advanced NSCLC treated with chemotherapy,but it needs further validation before it can be widely used in clinical practice.展开更多
BACKGROUND Tracheal neoplasms represent less than 0.1%of all malignancies and have no established treatment guidelines.Surgical resection with reconstruction is the primary treatment.This study demonstrates successful...BACKGROUND Tracheal neoplasms represent less than 0.1%of all malignancies and have no established treatment guidelines.Surgical resection with reconstruction is the primary treatment.This study demonstrates successful treatment of concurrent lung and tracheal tumors using surgical excision and intraoperative photodynamic therapy(PDT),highlighting the effectiveness and safety of this approach.CASE SUMMARY A 74-year-old male with a history of smoking and chronic obstructive pulmonary disease was diagnosed with tracheal squamous cell carcinoma and right lower lobe adenocarcinoma.A multidisciplinary team created a treatment plan involving tumor resection and PDT.The tracheal tumor was removed through a tracheal incision and this was followed by intraluminal PDT.The trachea was repaired and a right lower lobectomy was performed.The patient received a second PDT treatment postoperatively and was discharged 10 d after the tracheal surgery,without complications.He then underwent platinum-based chemotherapy for lymphovascular invasion of lung cancer.Three-month postoperative bronchoscopy revealed normal tracheal mucosa with a scar at the resection site and no evidence of tumor recurrence in the trachea or lung.CONCLUSION Our case of concurrent tracheal and lung cancers was successfully treated with surgical excision and intraoperative PDT which proved safe and effective in this patient.展开更多
Lung oncogenesis relies on intracellular cysteine to overcome oxidative stress.Several tumor types,including non-small cell lung cancer(NSCLC),upregulate the system x-c cystine/glutamate antiporter(xCT)through overexp...Lung oncogenesis relies on intracellular cysteine to overcome oxidative stress.Several tumor types,including non-small cell lung cancer(NSCLC),upregulate the system x-c cystine/glutamate antiporter(xCT)through overexpression of the cystine transporter SLC7A11,thus sustaining intracellular cysteine levels to support glutathione synthesis.Nuclear factor erythroid 2-related factor 2(NRF2)serves as a master regulator of oxidative stress resistance by regulating SLC7A11,whereas Kelch-like ECH-associated protein(KEAP1)acts as a cytoplasmic repressor of the oxidative responsive transcription factor NRF2.Mutations in KEAP1/NRF2 and p53 induce SLC7A11 activation in NSCLC.Extracellular cystine is crucial in supplying the intracellular cysteine levels necessary to combat oxidative stress.Disruptions in cystine availability lead to iron-dependent lipid peroxidation,thus resulting in a type of cell death called ferroptosis.Pharmacologic inhibitors of xCT(either SLC7A11 or GPX4)induce ferroptosis of NSCLC cells and other tumor types.When cystine uptake is impaired,the intracellular cysteine pool can be sustained by the transsulfuration pathway,which is catalyzed by cystathionine-B-synthase(CBS)and cystathionine g-lyase(CSE).The involvement of exogenous cysteine/cystine and the transsulfuration pathway in the cysteine pool and downstream metabolites results in compromised CD8^(+)T cell function and evasion of immunotherapy,diminishing immune response and potentially reducing the effectiveness of immunotherapeutic interventions.Pyroptosis is a previously unrecognized form of regulated cell death.In NSCLCs driven by EGFR,ALK,or KRAS,selective inhibitors induce pyroptotic cell death as well as apoptosis.After targeted therapy,the mitochondrial intrinsic apoptotic pathway is activated,thus leading to the cleavage and activation of caspase-3.Consequently,gasdermin E is activated,thus leading to permeabilization of the cytoplasmic membrane and cell-lytic pyroptosis(indicated by characteristic cell membrane ballooning).Breakthroughs in KRAS G12C allele-specific inhibitors and potential mechanisms of resistance are also discussed herein.展开更多
BACKGROUND The development of anaplastic lymphoma kinase(ALK)-tyrosine kinase inhibitors(TKIs)has remarkably improved the prognosis of patients with ALK-positive advanced non-small cell lung cancer(NSCLC).Alectinib,th...BACKGROUND The development of anaplastic lymphoma kinase(ALK)-tyrosine kinase inhibitors(TKIs)has remarkably improved the prognosis of patients with ALK-positive advanced non-small cell lung cancer(NSCLC).Alectinib,the second-generation ALK-TKI,has been approved as first-line treatment for advanced or metastatic NSCLC patients with ALK rearrangement.Neoadjuvant therapy can achieve tumor downstaging and eradicate occult lesions in patients with potentially resectable disease.Whether neoadjuvant alectinib can be a conversion therapy in ALK-positive advanced NSCLC patients remains unclear.CASE SUMMARY A 41-year-old man was pathologically diagnosed with locally advanced ALKpositive stage IIIB NSCLC.Alectinib was prescribed to induce tumor downstaging and facilitate the subsequent surgical resection.The tumor was successfully downstaged and pathological complete response was achieved.Left upper lobectomy with mediastinal lymphadenectomy was performed after tumor downstaging.The patient has continued to receive alectinib as adjuvant therapy during postoperative follow-up with a recurrence-free survival of 29 mo as of writing this report.CONCLUSION This case sheds light on the feasibility and safety of alectinib as a neoadjuvant treatment for stage IIIB NSCLC patients with ALK rearrangement.Its efficacy needs to be validated in prospective clinical trials.展开更多
基金supported by a grant from the National Science Foundation(Grant number 81102857)
文摘Objective To investigate the effects of bisdemethoxycurcumin(BDMC) on non-small cell lung cancer(NSCLC) cell line, A549, and the highly metastatic lung cancer 95 D cells. Methods CCK-8 assay was used to assess the effect of BDMC on cytotoxicity. Flow cytometry was used to evaluate apoptosis. Western blot analysis, electron microscopy, and quantification of GFP-LC3 punctuates were used to test the effect of BDMC on autophagy and apoptosis of lung cancer cells. Results BDMC inhibited the viability of NSCLC cells, but had no cytotoxic effects on lung small airway epithelial cells(SAECs). The apoptotic cell death induced by BDMC was accompanied with the induction of autophagy in NSCLC cells. Blockage of autophagy by the autophagy inhibitor 3-methyladenine(3-MA) repressed the growth inhibitory effects and induction of apoptosis by BDMC. In addition, BDMC treatment significantly decreased smoothened(SMO) and the transcription factor glioma-associated oncogene 1(Gli1) expression. Furthermore, depletion of Gli1 by si RNA and cyclopamine(a specific SMO inhibitor) induced autophagy. Conclusion Aberrant activation of Hedgehog(Hh) signaling has been implicated in several human cancers, including lung cancers. The present findings provide direct evidence that BDMC-induced autophagy plays a pro-death role in NSCLC, in part, by inhibiting Hedgehog signaling.
文摘Apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand(TRAIL) can be regulated by the epidermal growth factor(EGF) signaling pathway.In this study,recombinant adenoviral vectors that encode TRAIL gene from the hTERT/RGD promoter(AdTRAIL) was combined with drugs including gefitinib,elotinib,and cetuximab that inhibit EGFR and the EGF signaling pathway in non-small cell lung cancer(NSCLC) cell lines to investigate their antitumor activity.In vitro,compared to single reagent,AdTRAIL combined with EGFR inhibitors reduced proliferation and enhanced apoptosis in H460,A549,and SW1573 cell lines.Western blot results suggested that these effects were relative to up-regulation of pro-apoptosis protein BAX and down-regulation of p-AKT.In vivo,AdTRAIL combined with cetuximab resulted in a significant growth reduction in H460 xenografts without damage to the main organs of nude mice.Histological examination and TUNEL analyses of xenografts showed that cetuximab enhanced cell apoptosis induced by AdTRAIL.These results indicate that EGFR inhibitors enhanced AdTRAIL anti-tumor activity in NSCLC cell lines and that inhibiting the AKT pathway played an important role in this enhancement.
基金the National Natural Science Foundation of China(81872863)the Major Scientific Fund Project of Heilongjiang Province(ZD2019H001).
文摘Background:Apelin,an endogenous ligand of G-protein coupled receptor(GPCR),is a secreted peptide involved in the development of various tumors.However,the relationship between apelin and non-small cell lung cancer(NSCLC)is not quite clear.This study was designed to investigate the effect and mechanism of apelin on cell proliferation,migration and invasion of NSCLC cells.Methods:Twelve NSCLC specimens were collected for hematoxylin-eosin(HE)staining and immunohistochemistry analyses.Cell proliferation was examined by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)and cell migration and invasion were assessed using wound-healing and transwell assays.The subcellular location of yes associated protein 1(YAP1)in A549 cells was determined by immunofluorescence.The mRNA and protein levels in NSCLC tissues and cell lines were measured by qRT-PCR and western blot,respectively.Results:Apelin was upregulated in tumor tissues compared with the adjacent tissues.Apelin promoted proliferation,migration,and invasion of A549 and H460 cells,which was reversed by competitive apelin receptor(APJ)antagonist ML221.Additionally,apelin upregulated YAP1 expression,whereas silence of YAP1 by small interfering RNA(siRNA)attenuated apelin-induced cell proliferation,migration and invasion and suppressed epithelial-mesenchymal transition progression.Conclusion:Apelin promotes NSCLC cells proliferation,migration,and invasion by modulating YAP1 and might be a potential therapeutic target for NSCLC treatment.
文摘Objective The aim of this study was to explore the mechanism behind lncRNA small nucleolar RNA host gene 19(lncRNA SNHG19)/microrNA-299-5P(miR-299-5p)/mitogen-activated protein kinase 6(MAPK6)signaling axis promoting metastasis of non-small cell lung cancer(NSCLC).Methods To analyze the abnormal expression of lncRNAs in NSCLC,50 surgically resected NSCLC and adjacent tissue samples were collected from August 2021 to August 2022.The mRNA expression levels of lncRNA SNHG19,Mir-299-5p,and MAPK6 were detected by qRT-PCR.The functions of lncRNA SNHG19,Mir-299-5p and MAPK6 were investigated by CCK-8,clone formation,EdU,scratch,Transwell western blotting(WB)and in vivo xenograft assay.RNA fluorescence in-situ hybridization(FISH),RNA pull-down,dual luciferase reporter,and RNA co-immunoprecipitation assays were used to explore the mechanism of action between lncRNA SNHG19,miR-299-5p,and MAPK6.Results High expression of lncRNA SNHG19 was correlated with poor prognosis,tumor size,lymph node metastasis,and TNM stage in NSCLC patients(P<0.05).Cell function experiments showed that lncRNA SNHG19 could improve the proliferation,clone formation,migration,and invasion ability of A549 cells both in vitro and in vivo(all P<0.05)and increased the relative expression levels of vimentin and MAPK6(P<0.05).The relative expression level of E-cadherin was decreased(P<0.05).lncRNA SNHG19 can interact with Mir-299-5p and regulate the expression level of MAPK6.Conclusion lncRNA SNHG19 is upregulated in NSCLC tissues and cells,and its high expression is associated with tumor progression and poor survival.Moreover,it can act as a molecular sponge for Mir-299-5p to regulate MAPK6 expression and promote the proliferation and metastasis of A549 cells.
文摘Purpose Lung cancer is one of the most aggressive cancer types, and is the leading cause of cancer-related deaths worldwide. Isothiocyanates are natural compounds found in
基金supported by the Beijing Outstanding Young Scientist Program(No.BJJWZYJH01201910005017)the National Natural Science Foundation of China(Nos.22127805 and 22206008).
文摘Patients with epidermal growth factor receptor(EGFR)wild-type non-small cell lung cancer(NSCLC)often show primary resistance to gefitinib therapy.It is thus necessary to study the metabolism of gefitinib in NSCLC cells to comprehensively reveal the reasons for the primary resistance of tumors.Herein,we develop a platform for studying drug metabolism heterogeneity based on single-cell mass spectrometry(sDMH-scMS)by integrating living-cell electrolaunching ionization MS(ILCEI-MS)and high-performance liquid chromatography-MS(HPLC-MS)analysis,and the primary resistance of NSCLC cells to gefitinib was studied using this platform.The ILCEI-MS analysis showed that approximately 11.9%of NSCLC single cells contained the gefitinib metabolite M11;HPLC-MS detection diluted the intensity of M11 in subpopulations and concealed the heterogeneity of drug metabolism in tumor single cells.The intensity of gefitinib in EGFR wild-type A549 cells was markedly lower than in mutant PC9 cells,and the intensity of gefitinib metabolites was significantly higher than in PC9 cells,suggesting that the primary resistance of NSCLC cells is related to gefitinib metabolism.Moreover,the combination of gefitinib and the drug-metabolizing enzyme inhibitorα-naphthoflavone was shown to overcome the primary resistance of the NSCLC cells.Overall,the results of this study are expected to be applicable for clinical drug resistance diagnosis and treatment at the single-cell level.
基金supported by grants from the National Natural Science Foundation of China(No.82271755,No.81871230)Peking University People's Hospital Scientific Research Development Funds(RZ 2022-06).
文摘Objective This study aimed to investigate the changes of follicular helper T(TFH)and follicular regulatory T(TFR)cell subpopulations in patients with non-small cell lung cancer(NSCLC)and their significance.Methods Peripheral blood was collected from 58 NSCLC patients at different stages and 38 healthy controls.Flow cytometry was used to detect TFH cell subpopulation based on programmed death 1(PD-1)and inducible co-stimulator(ICOS),and TFR cell subpopulation based on cluster determinant 45RA(CD45RA)and forkhead box protein P3(FoxP3).The levels of interleukin-10(IL-10),interleukin-17a(IL-17a),interleukin-21(IL-21),and transforming growth factor-β(TGF-β)in the plasma were measured,and changes in circulating B cell subsets and plasma IgG levels were also analyzed.The correlation between serum cytokeratin fragment antigen 21-1(CYFRA 21-1)levels and TFH,TFR,or B cell subpopulations was further explored.Results The TFR/TFH ratio increased significantly in NSCLC patients.The CD45RA^(+)FoxP3^(int) TFR subsets were increased,with their proportions increasing in stages Ⅱ to Ⅲ and decreasing in stage IV.PD-1^(+)ICOS+TFH cells showed a downward trend with increasing stages.Plasma IL-21 and TGF-β concentrations were increased in NSCLC patients compared with healthy controls.Plasmablasts,plasma IgG levels,and CD45RA^(+)FoxP3^(int) TFR cells showed similar trends.TFH numbers and plasmablasts were positively correlated with CYFRA 21-1 in stages Ⅰ-Ⅲ and negatively correlated with CYFRA 21-1 in stage IV.Conclusion Circulating TFH and TFR cell subpopulations and plasmablasts dynamically change in different stages of NSCLC,which is associated with serum CYFRA 21-1 levels and reflects disease progression.
基金Supported by the Scientific Research Foundation of Peking University Shenzhen Hospital,No.KYQD2021096the National Natural Science Foundation of China,No.81972829Precision Medicine Research Program of Tsinghua University,No.2022ZLA006.
文摘BACKGROUND This study was designed to investigate the clinical outcomes of enhanced recovery after surgery(ERAS)in the perioperative period in elderly patients with nonsmall cell lung cancer(NSCLC).AIM To investigate the potential enhancement of video-assisted thoracic surgery(VATS)in postoperative recovery in elderly patients with NSCLC.METHODS We retrospectively analysed the clinical data of 85 elderly NSCLC patients who underwent ERAS(the ERAS group)and 327 elderly NSCLC patients who received routine care(the control group)after VATS at the Department of Thoracic Surgery of Peking University Shenzhen Hospital between May 2015 and April 2017.After propensity score matching of baseline data,we analysed the postoperative stay,total hospital expenses,postoperative 48-h pain score,and postoperative complication rate for the 2 groups of patients who underwent lobectomy or sublobar resection.RESULTS After propensity score matching,ERAS significantly reduced the postoperative hospital stay(6.96±4.16 vs 8.48±4.18 d,P=0.001)and total hospital expenses(48875.27±18437.5 vs 55497.64±21168.63 CNY,P=0.014)and improved the satisfaction score(79.8±7.55 vs 77.35±7.72,P=0.029)relative to those for routine care.No significant between-group difference was observed in postoperative 48-h pain score(4.68±1.69 vs 5.28±2.1,P=0.090)or postoperative complication rate(21.2%vs 27.1%,P=0.371).Subgroup analysis showed that ERAS significantly reduced the postoperative hospital stay and total hospital expenses and increased the satisfaction score of patients who underwent lobectomy but not of patients who underwent sublobar resection.CONCLUSION ERAS effectively reduced the postoperative hospital stay and total hospital expenses and improved the satisfaction score in the perioperative period for elderly NSCLC patients who underwent lobectomy but not for patients who underwent sublobar resection.
基金National Natural Science Foundation of China(No.81873396)Capital Health Development Research Project(No.2018-2-4065)Project of China-Japan Friendship Hospital(No.2018-HX-26)。
文摘Owing to significantly prolonged survival,targeted therapy has become standardized recommendation for advanced non-small cell lung cancer patients with mutated driver genes.However,the genetic status of lung cancer patients is dynamic.By dynamically monitoring the evolution of genes status,differential genes and concomitant genes related to progressive disease could be confirmed early,so as to achieve a more accurate and comprehensive insight of the whole process management of targeted therapy for lung cancer patients.Under the guidance of accurate genetic testing results,it is helpful to provide patients with more effective,long-term,and stable individualized targeted therapy.
文摘Actin, a highly conserved protein, plays a dominant role in Non-small cell lung cancer (NSCLC). Late diagnosis and the aggressive nature of NSCLC pose a significant threat. Studying the clinic pathological properties of NSCLC proteins is a potential alternative for developing treatment strategies. Towards this, 35 downregulated actin cytoskeletal proteins on NSCLC prognosis and treatment were studied by examining their protein-protein interactions, gene ontology enrichment terms, and signaling pathways. Using PubMed, various proteins in NSCLC were identified. The protein-protein interactions and functional associations of these proteins were examined using the STRING database. The focal adhesion signaling pathway was selected from all available KEGG and Wiki pathways because of its role in regulating gene expression, facilitating cell movement and reproduction, and significantly impacting NSCLC. The protein-protein interaction network of the 35 downregulated actin cytoskeleton proteins revealed that ACTG1, ACTR2, ACTR3, ANXA2, ARPC4, FLNA, TLN1, CALD1, MYL6, MYH9, MYH10, TPM1, TPM3, TPM4, PFN1, IQGAP1, MSN, and ZXY exhibited the highest number of interactions. Whereas HSPB1, CTNNA1, KRT17, KRT7, FLNB, SEPT2, and TUBA1B displayed medium interactions, while UTRN, TUBA1B, and DUSP23 had relatively fewer interactions. It was discovered that focal adhesions are critical in connecting membrane receptors with the actin cytoskeleton. In addition, protein kinases, phosphatases, and adapter proteins were identified as key signaling molecules in this process, greatly influencing cell shape, motility, and gene expression. Our analysis shows that the focal adhesion pathway plays a crucial role in NSCLC and is essential for developing effective treatment strategies and improving patient outcomes.
基金supported by the Natural Science Foundation of Hubei Province(no.2021CFB372 to Hua Xiong).
文摘Lung cancer is the leading cause of cancer-related deaths globally.In recent years,with the widespread use of genetic testing,epidermal growth factor receptor–tyrosine kinase inhibitor(EGFR-TKI)–targeted drugs have been efficacious to patients with lung adenocarcinoma exhibiting EGFR mutations.However,resistance to treatment is inevitable and eventually leads to tumor progression,recurrence,and reduction in the overall treatment efficacy.Lung cancer stem cells play a crucial role in the development of resistance toward EGFR-TKI–targeted therapy for lung adenocarcinoma.Lung cancer stem cells possess self-renewal,multilineage differentiation,and unlimited proliferation capabilities,which efficiently contribute to tumor formation and ultimately lead to tumor recurrence andmetastasis.In this study,we evaluated the origin,markers,stemness index,relevant classic studies,resistance mechanisms,related signaling pathways,and strategies for reversing lung cancer stem cell resistance to EGFR-TKIs to provide new insights on delaying or reducing resistance and to improve the treatment efficacy of patients with EGFR-mutated lung adenocarcinoma in the future.
基金supported by the National Natural Science Foundation of China(Grant No.:82072593).
文摘In non-small cell lung cancer(NSCLC),the heterogeneity promotes drug resistance,and the restricted expression of programmed death-ligand 1(PD-L1)limits the immunotherapy benefits.Based on the mechanisms related to translation regulation and the association with PD-L1 of methyltransferaselike 3(METTL3),the novel small-molecule inhibitor STM2457 is assumed to be useful for the treatment of NSCLC.We evaluated the efficacy of STM2457 in vivo and in vitro and confirmed the effects of its inhibition on disease progression.Next,we explored the effect of STM2457 on METTL3 and revealed its effects on the inhibition of catalytic activity and upregulation of METTL3 protein expression.Importantly,we described the genome-wide characteristics of multiple omics data acquired from RNA sequencing,ribosome profiling,and methylated RNA immunoprecipitation sequencing data under STM2457 treatment or METTL3 knockout.We also constructed a model for the regulation of the translation of METTL3 and PD-L1.Finally,we found PD-L1 upregulation by STM2457 in vivo and in vitro.In conclusion,STM2457 is a potential novel suppressor based on its inhibitory effect on tumor progression and may be able to overcome the heterogeneity based on its impact on the translatome.Furthermore,it can improve the immunotherapy outcomes based on PDL1 upregulation in NSCLC.
基金Local Science and Technology Development Funds Projects in Anhui Province(No.2020b07030008)。
文摘Objective:To explore the mechanism of tapinarof inhibiting proliferation and promoting apoptosis of non-small cell lung cancer A549 cell.Methods:The proliferative ability of non-small cell lung cancer cells A549 and H1299 was detected by clonal formation assay,and the cell viability of non-small cell lung cancer cells A549 was detected by CCK-8 assay.A549 cells were treated with different concentrations of tapinarof(0,5,10,20)μmol/L for 24 h.The effects of tapinarof on the cell cycle of A549 were detected by flow cytometry using PI single dye method.Western blot assay was used to detect the effect of benzene-moder on the expression of cycle-associated protein P21 and CDK2.A549 cells were treated with different concentrations of tapinarof(0,10,20,40)μmol/L for 48 h.Annexin V-FITC and PI double staining were used to detect the effect of tapinarof on apoptosis of A549 cells.Western blot assay was used to detect the effects of different concentrations of tapinarof on expression of apoptosis-related proteins,cleaved-caspase 3 and cleaved-PARP.Western blot analysis was performed to determine the expression of p-AKT and FOXO1 in A549 cells at different concentrations(0,5,10,20)μmol/L.Results:The results of clonal formation experiment showed that 40μmol/L tapinarof could completely inhibit the proliferation of A549 and H1299 cells.CCK-8 assay showed that compared with the control group(0μmol/L),A549 cell activity decreased gradually with the increase of tapinarof concentration.A549 cells were stained with Annexin-FITC/PI.Flow cytometry showed that the apoptosis rate of A549 cells increased with the increase of tapinarof treatment concentration(40μmol/L tapinarof treatment,P<0.001).After treatment with tapinarof for 48 h,the protein expression of cleaved-caspase 3 and cleaved-PARP in A549 cells was increased,compared with control group(0μmol/L).Flow cytometry after PI staining of A549 cells showed that tapinarof induced A549 cell arrest in G1 phase.In A549 cells treated with tapinarof for 24 h,the expression of P21 protein was increased and CDK2 decreased.The phosphorylation level of AKT was significantly inhibited and the expression level of FOXO1 was increased in A549 cells treated with phenylenmode at different concentrations.Conclusion:Tapinarof inhibits the proliferation of A549 cells and induces apoptosis,which may be related to the AKT/FOXO1 signaling pathway.
基金funded by the National Natural Science Foundation of China(Grant Nos.81972796,82272845,81972863,and 82030082)the Key Research and Development Program of Shandong(Major Science&Technology Innovation Project Grant No.2021SFGC0501)+1 种基金the CSCO-Haosen Foundation(Grant No.Y-HS202102-0089)the CSCO-Xinda Foundation(Grant No.Y-XD202001-0008)。
文摘Maintenance immunotherapy after concurrent chemoradiotherapy remains the standard therapeutic approach in patients with unresectable locally advanced non-small cell lung cancer(LA-NSCLC).The efficacy of pembrolizumab without chemotherapy in stage IV NSCLC has incited interest in similar approaches for LA-NSCLC.Several recent investigations involving the synergistic potential of immunotherapy combined with radiotherapy(i RT)have generated encouraging results.This review discusses the existing studies and prospective directions of chemotherapy-free i RT strategies in unresectable LA-NSCLC.Although the initial findings of chemotherapy-free i RT strategies have shown promising efficacy,we must consider the methodologic limitations of current studies and the myriad of challenges that accompany the implementation of chemotherapy-free i RT.These challenges include determining the optimal dose and fractionation,precise target volume delineation,and identification of additional suitable patient cohorts.Furthermore,the feasibility of chemotherapy-free i RT as a novel treatment modality for select patients with LA-NSCLC is contingent upon validation through randomized phase III trials.
文摘Objective The combination of stereotactic body radiation therapy(SBRT)and immune checkpoint inhibitors(ICIs)is actively being explored in advanced non-small-cell lung cancer(NSCLC)patients.However,little is known about the optimal fractionation and radiotherapy target lesions in this scenario.This study investigated the effect of SBRT on diverse organ lesions and radiotherapy dose fractionation regimens on the prognosis of advanced NSCLC patients receiving ICIs.Methods The medical records of advanced NSCLC patients consecutively treated with ICIs and SBRT were retrospectively reviewed at our institution from Dec.2015 to Sep.2021.Patients were grouped according to radiation sites.Progression-free survival(PFS)and overall survival(OS)were recorded using the Kaplan-Meier method and compared between different treatment groups using the log-rank(Mantel-Cox)test.Results A total of 124 advanced NSCLC patients receiving ICIs combined with SBRT were identified in this study.Radiation sites included lung lesions(lung group,n=43),bone metastases(bone group,n=24),and brain metastases(brain group,n=57).Compared with the brain group,the mean PFS(mPFS)in the lung group was significantly prolonged by 13.3 months(8.5 months vs.21.8 months,HR=0.51,95%CI:0.28–0.92,P=0.0195),and that in the bone group prolonged by 9.5 months with a 43%reduction in the risk of disease progression(8.5 months vs.18.0 months,HR=0.57,95%CI:0.29–1.13,P=0.1095).The mPFS in the lung group was prolonged by 3.8 months as compared with that in the bone group.The mean OS(mOS)in the lung and bone groups was longer than that of the brain group,and the risk of death decreased by up to 60%in the lung and bone groups as compared with that of the brain group.When SBRT was concurrently given with ICIs,the mPFS in the lung and brain groups were significantly longer than that of the bone group(29.6 months vs.16.5 months vs.12.1 months).When SBRT with 8–12 Gy per fraction was combined with ICIs,the mPFS in the lung group was significantly prolonged as compared with that of the bone and brain groups(25.4 months vs.15.2 months vs.12.0 months).Among patients receiving SBRT on lung lesions and brain metastases,the mPFS in the concurrent group was longer than that of the SBRT→ICIs group(29.6 months vs.11.4 months,P=0.0003 and 12.1 months vs.8.9 months,P=0.2559).Among patients receiving SBRT with<8 Gy and 8–12 Gy per fraction,the mPFS in the concurrent group was also longer than that of the SBRT→ICIs group(20.1 months vs.5.3 months,P=0.0033 and 24.0 months vs.13.4 months,P=0.1311).The disease control rates of the lung,bone,and brain groups were 90.7%,83.3%,and 70.1%,respectively.Conclusion The study demonstrated that the addition of SBRT on lung lesions versus bone and brain metastases to ICIs improved the prognosis in advanced NSCLC patients.This improvement was related to the sequence of radiotherapy combined with ICIs and the radiotherapy fractionation regimens.Dose fractionation regimens of 8–12 Gy per fraction and lung lesions as radiotherapy targets might be the appropriate choice for advanced NSCLC patients receiving ICIs combined with SBRT.
基金Research and Cultivation Foundation of Hainan Medical College(HYPY2020022)Hainan Natural Science Foundation Youth fund(822QN482)+1 种基金Doctoral Research Fund project of Hainan Cancer Hospital(2022BS04)Key R&D projects in Hainan Province(ZDYF2021SHFZ244)。
文摘Objective:To investigate the prognostic value of radiomics features based on ^(18)F-FDG PET/CT imaging for advanced non-small cell lung cancer(NSCLC)treated with chemotherapy.Methods:A sample of 146 NSCLC patients stagedⅢor stageⅣwere included in this retrospective study who received ^(18)F-FDG PET/CT before treatment.All patients were treated with standardized chemotherapy after PET/CT examination and were divided into training group and validation group in an 8:2 ratio randomly.Radiomics features were extracted.In the training group,the minimum absolute contraction and selection operator(LASSO)algorithm and Cox risk proportional regression model were used to screen radiomics and clinical prognostic factors of progression-free survival(PFS).The radiomic model,clinical model and complex model were established respectively.The corresponding scores were calculated,then verified in the validation group.Results:The LASSO algorithm finally screened four radiomics features.ROC results showed that in the training group,the AUC of PFS predicted by the radiomics model was 0.746,and that in the verification group was 0.622.COX multivariate analysis finally included three clinical features related to PFS in NSCLC patients,namely pathological type,clinical stage and MTV30.The AUC for predicting PFS by clinical model,radiomics model and composite model were 0.746,0.753 and 0.716,respectively.The radiomics model had the highest diagnostic efficacy,and its sensitivity and specificity were 0.663 and 0.833,respectively.Delong test verified that there was no statistical difference in the predictive efficacy between the radiomics model and the composite model(Z=1.777,P=0.076)and the clinical imaging model(Z=0.323,P=0.747).Conclusion:The radiomics model based on PET/CT has a good predictive value for the prognosis of advanced NSCLC treated with chemotherapy,but it needs further validation before it can be widely used in clinical practice.
文摘BACKGROUND Tracheal neoplasms represent less than 0.1%of all malignancies and have no established treatment guidelines.Surgical resection with reconstruction is the primary treatment.This study demonstrates successful treatment of concurrent lung and tracheal tumors using surgical excision and intraoperative photodynamic therapy(PDT),highlighting the effectiveness and safety of this approach.CASE SUMMARY A 74-year-old male with a history of smoking and chronic obstructive pulmonary disease was diagnosed with tracheal squamous cell carcinoma and right lower lobe adenocarcinoma.A multidisciplinary team created a treatment plan involving tumor resection and PDT.The tracheal tumor was removed through a tracheal incision and this was followed by intraluminal PDT.The trachea was repaired and a right lower lobectomy was performed.The patient received a second PDT treatment postoperatively and was discharged 10 d after the tracheal surgery,without complications.He then underwent platinum-based chemotherapy for lymphovascular invasion of lung cancer.Three-month postoperative bronchoscopy revealed normal tracheal mucosa with a scar at the resection site and no evidence of tumor recurrence in the trachea or lung.CONCLUSION Our case of concurrent tracheal and lung cancers was successfully treated with surgical excision and intraoperative PDT which proved safe and effective in this patient.
基金supported by a Spanish Association Against Cancer(AECC)grant,(grant No.PROYE18012ROSE)support from Julián Santamaría Vali?o to the IOR Foundation。
文摘Lung oncogenesis relies on intracellular cysteine to overcome oxidative stress.Several tumor types,including non-small cell lung cancer(NSCLC),upregulate the system x-c cystine/glutamate antiporter(xCT)through overexpression of the cystine transporter SLC7A11,thus sustaining intracellular cysteine levels to support glutathione synthesis.Nuclear factor erythroid 2-related factor 2(NRF2)serves as a master regulator of oxidative stress resistance by regulating SLC7A11,whereas Kelch-like ECH-associated protein(KEAP1)acts as a cytoplasmic repressor of the oxidative responsive transcription factor NRF2.Mutations in KEAP1/NRF2 and p53 induce SLC7A11 activation in NSCLC.Extracellular cystine is crucial in supplying the intracellular cysteine levels necessary to combat oxidative stress.Disruptions in cystine availability lead to iron-dependent lipid peroxidation,thus resulting in a type of cell death called ferroptosis.Pharmacologic inhibitors of xCT(either SLC7A11 or GPX4)induce ferroptosis of NSCLC cells and other tumor types.When cystine uptake is impaired,the intracellular cysteine pool can be sustained by the transsulfuration pathway,which is catalyzed by cystathionine-B-synthase(CBS)and cystathionine g-lyase(CSE).The involvement of exogenous cysteine/cystine and the transsulfuration pathway in the cysteine pool and downstream metabolites results in compromised CD8^(+)T cell function and evasion of immunotherapy,diminishing immune response and potentially reducing the effectiveness of immunotherapeutic interventions.Pyroptosis is a previously unrecognized form of regulated cell death.In NSCLCs driven by EGFR,ALK,or KRAS,selective inhibitors induce pyroptotic cell death as well as apoptosis.After targeted therapy,the mitochondrial intrinsic apoptotic pathway is activated,thus leading to the cleavage and activation of caspase-3.Consequently,gasdermin E is activated,thus leading to permeabilization of the cytoplasmic membrane and cell-lytic pyroptosis(indicated by characteristic cell membrane ballooning).Breakthroughs in KRAS G12C allele-specific inhibitors and potential mechanisms of resistance are also discussed herein.
文摘BACKGROUND The development of anaplastic lymphoma kinase(ALK)-tyrosine kinase inhibitors(TKIs)has remarkably improved the prognosis of patients with ALK-positive advanced non-small cell lung cancer(NSCLC).Alectinib,the second-generation ALK-TKI,has been approved as first-line treatment for advanced or metastatic NSCLC patients with ALK rearrangement.Neoadjuvant therapy can achieve tumor downstaging and eradicate occult lesions in patients with potentially resectable disease.Whether neoadjuvant alectinib can be a conversion therapy in ALK-positive advanced NSCLC patients remains unclear.CASE SUMMARY A 41-year-old man was pathologically diagnosed with locally advanced ALKpositive stage IIIB NSCLC.Alectinib was prescribed to induce tumor downstaging and facilitate the subsequent surgical resection.The tumor was successfully downstaged and pathological complete response was achieved.Left upper lobectomy with mediastinal lymphadenectomy was performed after tumor downstaging.The patient has continued to receive alectinib as adjuvant therapy during postoperative follow-up with a recurrence-free survival of 29 mo as of writing this report.CONCLUSION This case sheds light on the feasibility and safety of alectinib as a neoadjuvant treatment for stage IIIB NSCLC patients with ALK rearrangement.Its efficacy needs to be validated in prospective clinical trials.
